The objective of this study is to determine how specific combinations of homing receptors control the localization and function of CD4+CD25+ regulatory T cells (Treg). As potent modulators of self-reactive T cells, Treg represent an exciting new therapeutic approach for the treatment of autoimmune disorders such as type 1 diabetes, multiple sclerosis, rheumatoid arthritis and Chron's disease. However, as a prerequisite to understanding how Treg function in vivo to control autoimmunity, it is essential to determine where Treg localize and what cell types they interact with. While Treg express diverse and heterogeneous patterns of lymphocyte homing receptors, the relationship between their homing receptor expression, their localization, and their ability to modulate organ-specific autoimmunity has not been explored experimentally. We hypothesize that Treg must localize to and function within specific lymphoid and non-lymphoid tissues in order to prevent autoimmunity;Here we propose a series of experiments to test this hypothesis, and determine how disrupting Treg localization impacts their functional ability to prevent systemic and organ-specific autoimmunity (aim 1) and their survival/homeostasis (aim 2). In addition, we will test the hypothesis that homing receptor expression defines Treg subsets targeted to lymphoid vs. non-lymphoid tissues that have distinct functional and homeostatic characteristics (aim 3). Determining the relationship between Treg homing and their ability to control autoimmunity is required to understand where these cells function in vivo, and how diverse populations of Treg may function at distinct sites to prevent the initiation and/or progression of autoimmunity. This has clear and direct implications in the clinical application of Treg to the prevention and treatment of human autoimmune and inflammatory diseases.